Karen Jameson

Prevalence of sarcopenia in community-dwelling older people in the UK using the European Working Group on Sarcopenia in Older People (EWGSOP) definition: findings from the Hertfordshire Cohort Study (HCS)

Introduction: sarcopenia is associated with adverse health outcomes. The aim of this study was to describe the prevalence of sarcopenia in community-dwelling older people in the UK using the European Working Group on Sarcopenia in Older People (EWGSOP) consensus definition. Methods: we applied the EWGSOP definition to 103 community-dwelling men participating in the Hertfordshire Sarcopenia Study (HSS) using both the lowest third of dual-energy X-ray absorptiometry (DXA) lean mass (LM) and the lowest third of skin-fold-based fat-free mass (FFM) as markers of low muscle mass. We also used the FFM approach among 765 male and 1,022 female participants in the Hertfordshire Cohort Study (HCS). Body size, physical performance and self-reported health were compared in participants with and without sarcopenia. Results: the prevalence of sarcopenia in HSS men (mean age 73 years) was 6.8% and 7.8% when using the lowest third of DXA LM and FFM, respectively. DXA LM and FFM were highly correlated (0.91, P < 0.001). The prevalence of sarcopenia among the HCS men and women (mean age 67 years) was 4.6% and 7.9%, respectively. HSS and HCS participants with sarcopenia were shorter, weighed less and had worse physical performance. HCS men and women with sarcopenia had poorer self-reported general health and physical functioning scores. Conclusions: this is one of the first studies to describe the prevalence of sarcopenia in UK community-dwelling older people. The EWGSOP consensus definition was of practical use for sarcopenia case finding. The next step is to use this consensus definition in other ageing cohorts and among older people in a range of health-care settings.

Diet and its relationship with grip strength in community-dwelling older men and women: the Hertfordshire cohort study.

OBJECTIVES: To examine relationships between diet and grip strength in older men and women and to determine whether prenatal growth modifies these relationships.

Relationship of vitamin D status to adult lung function and COPD

Background There is considerable interest in the possible role of vitamin D in respiratory disease, but only one population-based study has reported associations with lung function. Methods The cross-sectional relationships of total dietary vitamin D intake, serum 25 hydroxy vitamin D (25(OH)D) concentrations and three vitamin D receptor (VDR) polymorphisms (Apa1, Fok1 and Cdx2) with lung function and spirometrically-defined chronic obstructive pulmonary disease (COPD) were investigated in men and women aged 59–73 years in the Hertfordshire Cohort Study, UK. Results After controlling for confounders, total vitamin D intake was positively associated with forced expiratory volume in 1 s (FEV1; difference in FEV1 between top and bottom quintiles of intake 0.079 l (95% CI 0.02 to 0.14), p trend=0.007, n=2942), ratio of FEV1 to forced vital capacity (FEV1/FVC; p trend=0.008) and negatively associated with COPD (OR comparing top and bottom quintiles 0.57 (95% CI 0.38 to 0.87), p trend=0.02). In contrast, serum 25(OH)D concentrations were not related to FEV1 (p trend=0.89, n=1197) but were positively associated with COPD (p trend=0.046). VDR genotypes were unrelated to lung function and did not modify the effects of dietary intake or 25(OH)D concentrations on lung function. Conclusions The results of this study did not confirm a positive association between blood 25(OH)D concentrations and adult lung function. The apparent relationships with dietary vitamin D are likely to be explained by other highly correlated nutrients in the diet.

MUSCLE SIZE, STRENGTH AND PHYSICAL PERFORMANCE AND THEIR ASSOCIATIONS WITH BONE STRUCTURE IN THE HERTFORDSHIRE COHORT STUDY

Sarcopenia is associated with a greater fracture risk. This relationship was originally thought to be explained by an increased risk of falls in sarcopenic individuals. However, in addition, there is growing evidence of a functional muscle‐bone unit in which bone health may be directly influenced by muscle function. Because a definition of sarcopenia encompasses muscle size, strength, and physical performance, we investigated relationships for each of these with bone size, bone density, and bone strength to interrogate these hypotheses further in participants from the Hertfordshire Cohort Study. A total of 313 men and 318 women underwent baseline assessment of health and detailed anthropometric measurements. Muscle strength was measured by grip strength, and physical performance was determined by gait speed. Peripheral quantitative computed tomography (pQCT) examination of the calf and forearm was performed to assess muscle cross‐sectional area (mCSA) at the 66% level and bone structure (radius 4% and 66% levels; tibia 4% and 38% levels). Muscle size was positively associated with bone size (distal radius total bone area β = 17.5 mm2/SD [12.0, 22.9]) and strength (strength strain index (β = 23.3 mm3/SD [18.2, 28.4]) amongst women (p < 0.001). These associations were also seen in men and were maintained after adjustment for age, height, weight‐adjusted‐for‐height, limb‐length‐adjusted‐for‐height, social class, smoking status, alcohol consumption, calcium intake, physical activity, diabetes mellitus, and in women, years since menopause and estrogen replacement therapy. Although grip strength showed similar associations with bone size and strength in both sexes, these were substantially attenuated after similar adjustment. Consistent relationships between gait speed and bone structure were not seen. We conclude that although muscle size and grip strength are associated with bone size and strength, relationships between gait speed and bone structure and strength were not apparent in this cohort, supporting a role for the muscle‐bone unit.

Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region

Background and objectives Chronic widespread pain (CWP) is a common disorder affecting ∼10% of the general population and has an estimated heritability of 48–52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP. Methods We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain. Results The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10−7) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10−8, I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10−4). Conclusions We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.

Association of vitamin D status with knee pain and radiographic knee osteoarthritis

OBJECTIVE The objective of the present study was to explore the association of serum vitamin D concentration and polymorphism in the vitamin D receptor (VDR), with knee pain and radiographic knee osteoarthritis (OA) among men and women in a large population-based UK cohort study. METHODS Seven hundred and eighty-seven participants in the Hertfordshire Cohort Study (399 men, 388 women; mean age 65.6±2.7 years) underwent a questionnaire on knee pain and radiographic knee examination. This study examined the association of Fok1, Cdx2 and Apa1 polymorphism in the gene for the VDR and serum 25(OH)D concentration with knee pain and radiographic knee OA by a generalized estimating equations population averaged logistic regression analysis in the Hertfordshire Cohort Study. RESULTS There were no associations of Fok1, Cdx2 and Apa1 polymorphisms of the VDR with knee OA except for Aa for Apa1 compared with AA [Odds ratio (OR) 0.59, 95% confidence interval (CI) 0.36-0.95, P=0.031]. While, ff for Fok1 (OR 1.60, 95% CI 1.07-2.39, P=0.022) and AA for Cdx2 polymorphism (OR 2.21, 95% CI 1.07-4.56, P=0.032) was significantly associated with higher prevalence of knee pain compared with FF for Fok1 and GG for Cdx2, respectively. None of these are statistically significant after adjusting for the three polymorphisms tested. 25(OH)D level was not significantly associated with radiographic knee OA, while, low tertile of 25(OH)D level tended to be associated with knee pain compared with high tertile of 25(OH)D level. CONCLUSION The present cross-sectional study using a large-scale population from the Hertfordshire Cohort study indicated that vitamin D may be associated with pain rather than radiographic change, but the evidence for an association between vitamin D genetic variation and pain in knee OA is very weak in the present study. Further replication of our results will be required to elucidate the association of vitamin D and knee OA.

Obesity-susceptibility loci have a limited influence on birth weight: a meta-analysis of up to 28,219 individuals

BACKGROUND High birth weight is associated with adult body mass index (BMI). We hypothesized that birth weight and BMI may partly share a common genetic background. OBJECTIVE The objective was to examine the associations of 12 established BMI variants in or near the NEGR1, SEC16B, TMEM18, ETV5, GNPDA2, BDNF, MTCH2, BCDIN3D, SH2B1, FTO, MC4R, and KCTD15 genes and their additive score with birth weight. DESIGN A meta-analysis was conducted with the use of 1) the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk, Hertfordshire, Fenland, and European Youth Heart Study cohorts (n(max) = 14,060); 2) data extracted from the Early Growth Genetics Consortium meta-analysis of 6 genome-wide association studies for birth weight (n(max) = 10,623); and 3) all published data (n(max) = 14,837). RESULTS Only the MTCH2 and FTO loci showed a nominally significant association with birth weight. The BMI-increasing allele of the MTCH2 variant (rs10838738) was associated with a lower birth weight (β ± SE: -13 ± 5 g/allele; P = 0.012; n = 23,680), and the BMI-increasing allele of the FTO variant (rs1121980) was associated with a higher birth weight (β ± SE: 11 ± 4 g/allele; P = 0.013; n = 28,219). These results were not significant after correction for multiple testing. CONCLUSIONS Obesity-susceptibility loci have a small or no effect on weight at birth. Some evidence of an association was found for the MTCH2 and FTO loci, ie, lower and higher birth weight, respectively. These findings may provide new insights into the underlying mechanisms by which these loci confer an increased risk of obesity.

Clinical risk factors, bone density and fall history in the prediction of incident fracture among men and women

The FRAX(tr) algorithm uses clinical risk factors (CRF) and bone mineral density (BMD) to predict fracture risk but does not include falls history in the calculation. Using results from the Hertfordshire Cohort Study, we examined the relative contributions of CRFs, BMD and falls history to fracture prediction. We studied 2299 participants at a baseline clinic that included completion of a health questionnaire and anthropometric data. A mean of 5.5years later (range 2.9-8.8years) subjects completed a postal questionnaire detailing fall and fracture history. In a subset of 368 men and 407 women, bone densitometry was performed using a Hologic QDR 4500 instrument. There was a significantly increased risk of fracture in men and women with a previous fracture. A one standard deviation drop in femoral neck BMD was associated with a hazards ratio (HR) of incident fracture (adjusted for CRFs) of 1.92 (1.04-3.54) and 1.77 (1.16-2.71) in men and women respectively. A history of any fall since the age of 45years resulted in an unadjusted HR of fracture of 7.31 (3.78-14.14) and 8.56 (4.85-15.13) in men and women respectively. In a ROC curve analysis, the predictive capacity progressively increased as BMD and previous falls were added into an initial model using CRFs alone. Falls history is a further independent risk factor for fracture. Falls risk should be taken into consideration when assessing whether or not to commence medication for osteoporosis and should also alert the physician to the opportunity to target falls risk directly.

Role of the Nav1.7 R1150W amino acid change in susceptibility to symptomatic knee osteoarthritis and multiple regional pain.

To assess the genetic association of pain in patients with knee osteoarthritis (OA) and those with multiple regional pain with the R1150W variant in the α‐subunit of the voltage‐gated sodium channel NaV1.7.

A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus

Background Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. Aim To identify CNVs associated with osteoporotic bone fracture risk. Method We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. Results A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10−5). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. Conclusions These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.